Chronic oral trimethylamine-N-oxide administration induces experimental incipient atherosclerosis in non-genetically modified mice.

Atherosclerosis is a chronic inflammatory disease of the arterial wall involving inflammation, redox imbalance, and impaired cholesterol transport. A high level of trimethylamine-N-oxide (TMAO) produced by meat and fat metabolism are involved in atherosclerosis development, but the exact relationship with inflammation is not completely clear. The study aimed to identify a possible association between TMAO; atherosclerotic changes in the aortic root; oxidative stress; and inflammation quantified by highly sensitive C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α), and interleukin-1beta (IL-1ß) levels. TMAO dihydrate was administered via gastric gavage to 20 male Wistar rats for 90 days; one separate group received vehicle. The TMAO-treated animals were divided into two groups: one group received a low dose of TMAO (20 mg/day) and the other group received a high dose of TMAO (40 mg/day). Malondialdehyde (MDA), proinflammatory markers - IL-1ß, TNF-α, and hsCRP, total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, and glucose were assessed 30 and 90 days after TMAO administration. Additionally, conventional histopathology and immunohistochemistry for collagen I distribution were performed. MDA, hsCRP, TNF-α, and IL-1ß levels increased after 90 days of TMAO administration in conjunction with significant changes suggestive of incipient atherosclerosis and inflammation of the aortic root. The increase was higher in the group treated with 40 mg/day TMAO compared with the group treated with 20 mg/day TMAO. Additionally, blood levels of TMAO were significantly correlated with hsCRP, TNF-α, IL-1ß levels, but also with MDA, low HDL-cholesterol levels, and high triglyceride levels. The increase in MDA and inflammatory cytokines and modification of lipid metabolism markers may explain the pro-atherogenic effect of TMAO.

Characterization and biological effects of Hypericum extracts on experimentally-induced - anxiety, oxidative stress and inflammation in rats.

Anxiety disorders can associate with oxidative stress and immune system alterations. Our study aimed to chemically analyze Hypericum maculatum (HM) and Hypericum perforatum (HP) dry extracts and to evaluate their effects along with quercetin (Q), on brain oxidative stress biomarkers: malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD), inflammatory cytokines: interleukin-1α, (IL-1α), IL-1ß, regulated on activation normal T cell expressed and secreted (RANTES), interferon (IFN), monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein (MIP) and serum corticosterone levels. Nuclear transcription factor κB (NFκB) signaling pathway in the hippocampus and frontal lobe in rats with N-methyl-9H-pyrido[5,4-b]indole-3-carboxamide (FG-7142) experimental-induced anxiety were also investigated. The chemical analyses of total hypericins were performed by spectrophotometric analysis and hypericin, hyperforin and polyphenols derivatives were quantified by chromatographic methods. The animals were divided in 6 groups: carboxymethylcellulose 2% (CMC); CMC + FG; alprazolam (APZ) + FG; Q + FG; HM + FG; HP + FG. APZ (0.08 mg/kg b.w.), Q (30 mg/kg b.w.), HM and HP (350 mg/kg b.w.) were orally administered for 21 days. FG (7.5 mg/kg b.w.) was intraperitoneally (i.p.) injected in a single dose. Q and hypericum extracts (HpE) exerted anti-inflammatory (decreased IL-1α, IL-1ß, MCP1, IFN and MIP mainly in hippocampus) and antioxidant effects (decreased MDA levels, increased CAT and SOD activity), enhanced NFκB and pNFκB expressions in the brain and reduced serum corticosterone levels. Our findings suggest that HpE may improve anxiety-like behavior, offer brain protection by modulation of oxidative stress and inflammation, and can contribute to overall biological activity of natural compounds-rich diet.

Anti-inflammatory effects of Allium schoenoprasum L. leaves.

Allium schoenoprasum has antimicrobial and antifungal properties and is used to relieve pain from sunburn and sore throat. The aim of the present study was to evaluate the anti-inflammatory effects of the extracts from A. schoenoprasum leaves. A 1:1 (w:v) extract was prepared by a modified Squibb repercolation method. The total phenolic content of 68.5±2 g gallic acid aquivalent (GAE)/g plant was determined using the Folin-Ciocalteu method. The in vitro antioxidant activity was determined using the 1,1-diphenyl-2-picrylhydrazyl bleaching method (6.72±0.44 g/mg DPPH) and the trolox equivalent antioxidant capacity (132.8±23 g trolox eq./g plant) assay. Analysis of the extracts using the hemoglobin ascorbate peroxidase activity inhibition assay or the electron spin resonance did not yield signals above the detection limit. The anti-inflammatory effects of three extract concentrations (25%, 50%, 100%) were evaluated in vivo on a model turpentine oil-induced inflammation in rats. These three extracts were also evaluated in vitro for the ability to inhibit phagocytosis, the accumulation of total nitrites and nitrates in the serum, the total oxidative status, the total antioxidant response and the oxidative stress index. Pure extracts (100% concentration) had the best inhibitory activity on phagocytosis and oxidative stress. In conclusion, these results support the hypothesis that extracts from A. schoenoprasum leaves exert anti-inflammatory activities by inhibiting phagocytosis through the reduction of nitro-oxidative stress.

A pharmacokinetic drug interaction study between nebivolol and paroxetine in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: Nebivolol is a highly selective beta-blocker with additional vasodilator properties, widely used in the clinical practice for the treatment of hypertension and heart failure. Paroxetine is a second-generation antidepressant and a potent inhibitor of CYP2D6, the same isoenzyme involved in the metabolism of nebivolol. The objective of this study was to investigate the effect of multiple-dose paroxetine intake on the pharmacokinetics of nebivolol in healthy volunteers and its potential consequences upon nebivolol pharmacodynamics. METHODS: The study included 23 healthy subjects and was designed as an open-label, single-centre, non-randomized, two-period clinical trial. During period 1 (reference), each volunteer received a single dose of 5 mg nebivolol, whereas during period 2 (test), each volunteer received a single dose of 5 mg nebivolol and 20 mg paroxetine, after a pretreatment regimen with paroxetine (20-40 mg/day for 6 days). The pharmacokinetic parameters of nebivolol and its active metabolite were analysed by non-compartmental modelling. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest, after each nebivolol intake. RESULTS AND DISCUSSION: Pretreatment with paroxetine increased the mean peak plasma concentrations (Cmax ) for unchanged nebivolol (1·78 ± 1·17 vs. 4·24 ± 1·67 ng/mL) and for its active metabolite (0·58 ± 0·21 vs. 0·79 ± 0·24 ng/mL) compared to nebivolol alone. The time (tmax ) to reach Cmax was 1·37 ± 0·88 (h) and 3·11 ± 1·76 (h) for the parent compound and its active metabolite after nebivolol administered alone and 3·96 ± 1·76 (h), respectively, 7·33 ± 7·84 (h) after pretreatment with paroxetine. Also, the total areas under the curve (AUC0-∞ ) were significantly increased from 17·26 ± 43·06 to 106·20 ± 65·56 h ng/mL for nebivolol unchanged and 13·03 ± 11·29 to 74·56 ± 88·77 h ng/mL for its hydroxylated metabolite, before and after paroxetine intake. All the pharmacokinetic parameters presented statistically significant differences when paroxetine was administered with nebivolol. Nonetheless, statistical analysis did not show a significant difference between the vital signs measured during the two periods. WHAT IS NEW AND CONCLUSION: After pretreatment with paroxetine, the exposure to nebivolol was increased by 6·1-fold for the parent drug and 5·7-fold for the hydroxylated active metabolite. Paroxetine influenced nebivolol pharmacokinetics in healthy volunteers, but it did not have a significant effect on nebivolol pharmacodynamic parameters measured at rest, although the clinical relevance of this drug interaction needs further investigation.

Antioxidant, xanthine oxidase and lipoxygenase inhibitory activities and phenolics of Bauhinia rufescens Lam. (Caesalpiniaceae).

An aqueous acetone extract of the stem with the leaves of Bauhinia rufescens and its fractions were analysed for their antioxidant and enzyme-inhibitory activities, as well as their phytochemical composition. For measurement of the antioxidant activities, the 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azinobis(3-ethylbenzoline-6-sulphonate) and the ferric-reducing methods were used. The results indicated that the aqueous acetone, its ethyl acetate and n-butanol fractions possessed considerable antioxidant activity. Further, the xanthine oxidase and lipoxygenase inhibitory assays showed that the n-butanol fraction possessed compounds that can inhibit both these enzymes. In the phytochemical analysis, the ethyl acetate and the n-butanol fractions of the aqueous acetone extract were screened by HPLC-MS for their phenolic content. The results indicated the presence of hyperoside, isoquercitrin, rutin quercetin, quercitrin, p-coumaric and ferulic acids in the non-hydrolysed fractions. In the hydrolysed fractions, kaempferol, p-coumaric and ferulic acids were identified.

Food-drug interactions: grapefruit juice.

Food-drug interactions are increasingly recognized as important clinical events which may change significantly the bioavailability of oral administrated drugs. Grapefruit juice (GFJ) demonstrated multiple interactions with drugs leading to loss of the therapeutic effects or increased side-effects. GFJ decreases pre-systemic metabolism through a) competitive or mechanism-based inhibition of gut wall CYP3A4 isoenzymes and b) P-glycoprotein (P-gp), c) multidrug resistance protein-2 (MRP2) or d) organic anion-transporting polypeptide (OATP) inhibition. Although, GFJ presents high amounts of flavonoids (e.g. naringin, naringenin), furanocoumarins (e.g. 6',7'-dihydroxybergamottin, bergamottin) are the main chemicals involved in the pharmacokinetic interactions. As compounds of GFJ show additive or synergistic effects, all the major furanocoumarins are necessary for the maximal inhibitory effect. Also, related citrus fruits (sweeties, pummelo and sour orange) or various plants containing furanocoumarins may present pharmacological interactions, yet to be discovered.

Antioxidant, diuretic activities and polyphenol content of Stereospermum kunthianum Cham. (Bignoniaceae).

Stereospermum kunthianum was used for biological and phytochemical investigations. In biological studies, antioxidant activities were investigated with water, methanol and aqueous acetone extracts. Furthermore, the xanthine oxidase inhibitory activity and the diuretic activity of an aqueous acetone extract were evaluated. In the phytochemical investigations, the flavonoids and polyphenols were quantified spectrophotometrically in all extracts followed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis of an aqueous acetone extract. The 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing/antioxidant power (FRAP) and 2,2'-azinobis (3-ethylbenzoline-6-sulphonate (ABTS) methods have shown that the aqueous acetone extract presents the best antioxidant activities. This aqueous acetone extract was further proven to have interesting xanthine oxidase inhibitory activity, but only a weak diuretic activity. This aqueous acetone extract also possessed the highest phenolic and flavonoid contents. HPLC-MS analysis allowed identifying and quantifying, rutin, isoquercitrin, quercetin, hyperoside, quercitrin and luteolin and the glycosides of ferulic, sinapic p-coumaric acids and kaempferol, apigenin in aqueous-acetone extract.

Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: Ivabradine is a novel heart rate-lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. METHODS: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12-h period following drug administration, using a high-throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non-compartmental and compartmental analysis to determine if there were statistically significant differences. RESULTS AND DISCUSSION: In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C(max), t(max), were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC(0-∞)) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C(max) and AUC(0-∞) when ivabradine was administered with carbamazepine, whereas they were not for t(max), half-life and mean residence time. WHAT IS NEW AND CONCLUSION: T Carbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likely to be clinically significant.

Artemisinin evaluation in Romanian Artemisia annua wild plants using a new HPLC/MS method.

Artemisinin, a sesquiterpene lactone from Artemisia annua L., has received considerable attention in the last few decades as a potent antimalarial drug. Artemisinin has rather low toxicity; it is effective against drug-resistant Plasmodium species and against cerebral malaria. This study reports the development of a rapid and sensitive assay for the quantification of artemisinin in A. annua by reversed phase HPLC/MS. In the selected optimal experimental conditions, artemisinin exhibited a well-defined chromatographic peak with a retention time of 2 ± 0.2 min. The chromatographic signal shows a linear dependence with artemisinin concentration, enabling the use of this signal for artemisinin quantification according to the following regression equation: y = 2665.40x - 14697.61. The correlation coefficient (R(2)) was 0.9989. For every concentration within the range of the standard curve (0.1-2 µg mL(-1)), accuracy was between 95 and 104%. Artemisinin content in Romanian A. annua wild plants varies between 0.17 and 0.21% (dry weight basis).

Identification and quantification of phenolic compounds from Balanites aegyptiaca (L) Del (Balanitaceae) galls and leaves by HPLC-MS.

Balanites aegyptiaca is a tropical plant which is widely used for medicinal purposes in several African countries, including Burkina Faso. Despite its widespread use, little is known about its phenolic content. This study sought to carry out a screening of the polyphenols from the leaves and galls of B. aegyptiaca. A high-performance liquid chromatography-mass spectrometry method was used to investigate the phenolic content in the parts of the plant studied here. The phenolic acid profile showed the presence of gentisic, p-coumaric, caffeic, ferulic and sinapic acids in the crude and hydrolysed extracts. The flavonoids pattern showed hyperoside, isoquercitrin, rutoside and quercitrin in the crude extract of leaves. Myricetol, quercetol and kaempferol were found after acid hydrolysis of the leaves extract. Ferulic acid, isoquercitrin, rutoside and quercitrin were identified as major phenolic compounds in this study.

Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

PURPOSE: The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. METHODS: 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). RESULTS: The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. CONCLUSION: FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

Grapefruit juice--drug interactions: importance for pharmacotherapy.

In spite of known health benefits of grapefruit juice, its consumption in combination with drugs requires caution. The drugs most susceptible to pharmacokinetic interactions with clinical significance are those with narrow therapeutic index and low bioavailability due to important first-pass metabolism. Most vulnerable populations are elderly, cirrhotics, subjects with genetic polymorphisms and individuals taking other CYP3A4 inhibitors. The major drug classes that have been reported to present interactions with grapefruit juice are antiallergics, antibiotics, antimalaria drugs, anxiolytics, calcium channel blockers, HIV protease inhibitors, HMG-CoA reductase inhibitors; the degree of pharmacokinetic interaction varies among the compounds of the same class.

The study of some polyphenolic compounds from Melissa officinalis L. (Lamiaceae).

UNLABELLED: We proposed the analyses of polyphenolic coumpounds from the Melissa officinalis L. (Lamiaceae) leaves obtained from Medicinal Plant Collection of USAMV Cluj-Napoca. MATERIAL AND METHOD: The study was performed by using spectrophotometric (I) and HPLC methods (II). RESULTS: The vegetal product contains 0.64% flavonoids expressed in rutoside and 8,962% phenyl-propane derivatives expressed in caffeic acid (I). HPLC analyses (II) were made after extraction of studied compounds from leaves with ethyl-ether, ethyl acetate and 1-buthanol. These extracts were analyzed before and after the hydrolysis of compounds. There were identified 6 polyphenolic compounds: caftaric acid, caffeic acid, p-cumaric acid, ferulic acid, luteolin and apigenin. CONCLUSION: The extracted amount of these compounds in chosen solvents depending of their polarity.

New method for determination of dydrogesterone in human plasma for therapeutic drug monitoring in gynecological disorders.

UNLABELLED: A new simple, sensitive and selective liquid chromatography coupled with mass spectrometry (LC/MS) method for quantification of dydrogesterone in human plasma was validated. MATERIAL AND METHOD: The analytes was eluted in 1.3 minutes on a reversed phase column (Zorbax SB-C18, 100 mm x 3.0 mm I.D., 3.5 microm) under isocratic conditions using a mobile phase of a 20 : 80 (v/v) mixture of ammonium acetate 1 mM and acetonitrile. The flow rate was 1 mL/min at the column temperature of 35 degrees C. The detection of the analyte was in MS/ MS mode using an atmospheric pressure chemical ionization source (APCI+, m/z 313 > m/z 295). The sample preparation was very simple and rapid and consisted in plasma protein precipitation from 0.2 mL plasma using 0.6 mL methanol. RESULTS: Calibration curves were generated over the range of 5-150 ng/mL with values for coefficient of determination greater than 0.997 and by using a weighted (1/y) linear regression. The values of precision and accuracy were less than 12.5% and 7.5%, respectively, both for within- and between-run analysis. The mean recovery of the analyte was 99.8%. This is the first reported method for analysis dydrogesterone in human plasma that uses protein precipitation as sample processing procedure. The validated LC/MS method could be applied for determination of dydrogesterone in human plasma for therapeutic drug monitoring in gynecological disorders.

Fast determination of colchicine by TLC-densitometry from pharmaceuticals and vegetal extracts.

Colchicine, (S)-N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo-(a(-heptalen-7-yl)-acetamide, is the main alkaloid contained in Colchicum autumnale (meadow saffron). There are known colorimetric, spectrophotometric, volumetric, potentiometric, voltametric, gravimetric and various chromatographic methods for quantitative determination of colchicine, each of them presenting a series of advantages and disadvantages. As an alternative, we proposed the use of a densitometric determination for colchicine allowing the determination of this alkaloid from pharmaceutical products, as well from seeds of meadow saffron. The total alkaloid extract was separated by Thin-Layer Chromatography using Silicagel 60F(254) layers and a mixture of chloroform:acetone:diethylamine (5:4:1) as mobile phase. The same conditions were used for the determination from pharmaceutical products. Densitometric measurements were carried out at the absorption maximum (350 nm) of colchicine, the determinations being made by reflectance and by fluorescence. The peaks were optimized regarding to their area and shape by varying four scanning parameters (slit width and height, number of measurements and scanning speed). We established the calibration plot using pure colchicine in the range 50-600 ng mL(-1). The proposed method could be widely used in the pharmaceutical industry for the quick and accurate quantitative determination of colchicine because it eliminates the interferences given by other bioactive or degradation compounds. The method was characterized by validation parameters (linearity, accuracy, fidelity, sensitivity) and it was established its performances in comparison with an HPLC method and an official quantitative determination from the Romanian Pharmacopoeia X edition respectively.

[Quantification of caffeine from energy drinks with mass spectrometry method (LC/MS)]. / Determinarea cafeinei din bauturi energizante prin LC/MS.

A high performance liquid chromatography coupled with mass spectrometry method (LC/MS) for quantification of caffeine from energy drinks was elaborated. It was utilised a Zorbax SB-C18, 100 mm x 3.0 mm i.d., 3.5 microm column with a mobile phase containing methanol/ solution 0.2% formic acid in water. Detection and quantification of caffeine was based on monitoring the protonated molecular ion abundance (m/z 194.9). The quantification was made using the external standard method. The calibration curve were made on range 0.26-26 microg/ml for caffeine with a correlation coefficient greater than 0.995. There were analysed 12 energy drinks with a caffeine content between 13 and 34 mg/100 ml.

Preliminary HPLC study on some polyphenols of Geranium robertianum L. (Geraniaceae).

In order to continue our previous studies concerning Geranium robertianum L., herb Robert (Geraniaceae), we have realised a HPLC study of some polyphenols using an original method created by a group of young researchers from the University of Medicine and Pharmacy of Cluj-Napoca. We have identified and measured in the dried Geranii robertiani herba (harvested from Valea Runcului, district of Alba-Iulia) the following compounds: hyperoside (3.64 microg/100 mg), ellagic acid (7599.76 microg/100 mg), isoquercitrin (49.49 microg/100 mg), quercetrin (83.92 microg/100 mg), kaempferols (143.43 microg/100 mg), caftaric acid (166.92 microg/100 mg), rutoside (72.23 microg/100 mg). We have also analysed a hydrolysed sample of the same drug in which we have identified and measured: caffeic acid (6.62 microg/100 mg), ellagic acid (10550.65 microg/100 mg), quercetrin (203.44 microg/100 mg), kaempferols (231.80 microg/100 mg), caftaric acid (47.41 microg/100 mg). We have indirectly proved the presence of ellagic tannins (the amount of ellagic acid increases after acid hydrolise) and the existence of bi- or polycaffeoil derivatives (the caffeic acid is present only in the hydrolysed sample). The flavonoid aglycones exist in both forms: as free compounds and as part of the flavonoid molecules.

A pharmacokinetic interaction study between omeprazole and the H2-receptor antagonist ranitidine.

The effect of ranitidine pretreatment on the pharmacokinetics of omeprazole was investigated in 14 male human volunteers. Omeprazole (40 mg, gastroresistant pellets) was administered to the volunteers in a two-treatment study design, either alone or after 5 days pretreatment with b.i.d. doses of 150 mg ranitidine. Plasma concentrations of omeprazole were determined over a 24-hour period following drug administration, by a validated RP-HPLC method. Pharmacokinetic parameters were calculated with compartmental and non-compartmental analysis, using the computer program Kinetica (Inna Phase). In the two periods of treatments, the mean peak plasma concentrations Cmax were 730.8 ng/ml for omeprazole alone and 802.1 ng/ml for omeprazole co-administered with ranitidine (not significant). The time taken to reach the peak, Tmax, was 1.29 h and 1.42 h, respectively (not significant). The areas under the curve (AUC0-10) were 1,453.3 ng.h/ml and 1,736.8 ng.h/ml for the two periods of treatment; thus a greater AUC was obtained after pretreatment with multiple doses of ranitidine. Our data show that the pharmacokinetics of omeprazole might be inhibited by pretreatment with ranitidine; however, the clinical relevance of this interaction still has to be confirmed.

Congenital adrenal hyperplasia with female pseudohermaphroditism in a 26-year-old patient.

The paper presents the case of a 26-yr-old patient admitted for intersexuality. Clinical examination shows statural deficit, female phenotype, melanoderma, glabrous tegmina except for the pubic area presenting horizontally inserted pilosity, labioscrotum devoid of contents, pseudomicropenis with hypospadias. The Barr cytogenetic test is positive (56%) and hormone assay shows plasma cortisol at the lower limit and adrenal androgenic hormones and their metabolites in excess, suppressible by dexamethasone. The patient had a history of repeated admissions to intensive care units for severe dehydration, vomiting, diarrhea and collapse.

Cardiac disturbances in thyrotoxicosis: diagnosis, incidence, clinical features and management.

In the present paper we studied 403 patients with different etiopathogenic and clinical forms of thyrotoxicosis: toxic multinodular goiter (36.7%), toxic adenoma (4.9%), Graves' disease (27.04%), transient thyrotoxicosis (subacute thyroiditis, painless thyroiditis, Hashitoxicosis) (21.09%), T3-thyrotoxicosis (9.42%), thyrotoxicosis factitia (0.74%). Eighty-seven patients (21.5%) had cardiac disturbances. The following arrhythmias were most common: atrial fibrillation (4.00%), ventricular premature beats (2.77%), paroxysmal supraventricular tachycardia (2.23%), atrial flutter (1.00%). Congestive heart failure occurred in 10.42% of the cases. Paroxysmal tachyarrhythmias were converted to sinus rhythm in 90% of the subjects, by a selected and sustained treatment: drug therapy (carbimazole 30-40 mg/day, Lugol solution 1/2/20, 10-15 drops/day, beta-adrenergic blockers (propranolol--60-120 mg/24 hrs), calcium channel blockers (verapamil--40-60 mg/24 hrs), cardiac glycosides (deslanosid) or DC cardioversion. In order to prevent recurrences and/or complications, drug therapy was subsequently completed with subtotal thyroidectomy or radioactive iodine (131I) therapy. Thus, we succeeded in maintaining the patients in a euthyroid state, in sinus rhythm and with an adequate cardiovascular function in 95.4% of the cases.